Glucagon-like Peptide-2 Receptor Activation Engages Bad and Glycogen Synthase Kinase-3 in a Protein Kinase A-dependent Manner and Prevents Apoptosis following Inhibition of Phosphatidylinositol 3-Kinase

Activation of glucagon-like peptide-2 receptor (GLP-2R) signaling promotes expansion of the mucosal epithelium indirectly via activation of growth and anti-apoptotic pathways; however, the cellular mechanisms coupling direct GLP-2R activation to cell survival remain poorly understood. We now demonstrate that GLP-2, in a cycloheximide-insensitive manner, enhanced survival in baby hamster kidney cells stably transfected with the rat GLP-2R; reduced mitochondrial cytochrome c efflux; and attenuated the caspase-dependent cleavage of Akt, poly(ADP-ribose) polymerase, and β-catenin following inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002. The prosurvival effects of GLP-2 on LY294002-induced cell death were independent of Akt, p90Rsk, or p70 S6 kinase activation; were mimicked by forskolin; and were abrogated by inhibition of protein kinase A (PKA) activity. GLP-2 inhibited activation of glycogen synthase kinase-3 (GSK-3) through phosphorylation at Ser21 in GSK-3α and at Ser9 in GSK-3β in a PI3K-independent, PKA-dependent manner. GLP-2 reduced LY294002-induced mitochondrial association of endogenous Bad and Bax and stimulated phosphorylation of a transfected Bad fusion protein at Ser155 in a PI3K-independent, but H89-sensitive manner, a modification known to suppress Bad pro-apoptotic activity. These results suggest that GLP-2R signaling enhances cell survival independently of PI3K/Akt by inhibiting the activity of a subset of pro-apoptotic downstream targets of Akt in a PKA-dependent manner. Activation of glucagon-like peptide-2 receptor (GLP-2R) signaling promotes expansion of the mucosal epithelium indirectly via activation of growth and anti-apoptotic pathways; however, the cellular mechanisms coupling direct GLP-2R activation to cell survival remain poorly understood. We now demonstrate that GLP-2, in a cycloheximide-insensitive manner, enhanced survival in baby hamster kidney cells stably transfected with the rat GLP-2R; reduced mitochondrial cytochrome c efflux; and attenuated the caspase-dependent cleavage of Akt, poly(ADP-ribose) polymerase, and β-catenin following inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002. The prosurvival effects of GLP-2 on LY294002-induced cell death were independent of Akt, p90Rsk, or p70 S6 kinase activation; were mimicked by forskolin; and were abrogated by inhibition of protein kinase A (PKA) activity. GLP-2 inhibited activation of glycogen synthase kinase-3 (GSK-3) through phosphorylation at Ser21 in GSK-3α and at Ser9 in GSK-3β in a PI3K-independent, PKA-dependent manner. GLP-2 reduced LY294002-induced mitochondrial association of endogenous Bad and Bax and stimulated phosphorylation of a transfected Bad fusion protein at Ser155 in a PI3K-independent, but H89-sensitive manner, a modification known to suppress Bad pro-apoptotic activity. These results suggest that GLP-2R signaling enhances cell survival independently of PI3K/Akt by inhibiting the activity of a subset of pro-apoptotic downstream targets of Akt in a PKA-dependent manner. glucagon-like peptide GLP-2 receptor rat GLP baby hamster kidney phorbol 12-myristate 13-acetate phosphatidylinositol 3-kinase glycogen synthase kinase-3 extracellular signal-regulated kinase protein kinase A G protein-coupled receptor The endocrine pancreas and intestinal endocrine system produce peptide hormones that regulate food intake, gastrointestinal motility, acid secretion, nutrient transit, and both nutrient absorption and disposal. The majority of these actions are rapid, occur within minutes following activation of distinct hormone-specific G protein-coupled receptors, and serve to modulate the intake and assimilation of energy in both the fasting and postprandial states. The proglucagon gene is expressed in both the endocrine pancreas and intestine and, following tissue-specific processing of proglucagon, gives rise to multiple peptides, including glucagon in the endocrine pancreas and glucagon-like peptide-1 (GLP-1),1 and glucagon-like peptide-2 (GLP-2) in the intestine (1Drucker D.J. Endocrinology. 2001; 142: 521-527Crossref PubMed Scopus (310) Google Scholar). Glucagon acts to maintain energy homeostasis through the hepatic control of glycogenolysis and gluconeogenesis and serves as the primary counter-regulatory hormone that opposes insulin action and thereby prevents hypoglycemia (2Gerich J. Langlois M. Noacco C. Karam J. Forsham P. Science. 1973; 182: 171-173Crossref PubMed Scopus (544) Google Scholar). In contrast, GLP-1 enhances the disposal of ingested nutrients via inhibition of glucagon secretion and stimulation of insulin secretion from the islet β cell. The acute metabolic actions of GLP-2 are less well understood; however, exogenous administration of GLP-2 inhibits gastric acid secretion and gastric motility, reduces intestinal permeability, and enhances intestinal hexose transport in rodentsin vivo (3Drucker D.J. J. Clin. Endocrinol. Metab. 2001; 86: 1759-1764Crossref PubMed Scopus (94) Google Scholar). The most striking consequence of GLP-2 action is expansion of the small bowel mucosal epithelium. GLP-2 administration stimulates crypt cell proliferation, increases crypt and villus height, and augments mucosal surface area in both rats and mice (4Drucker D.J. Ehrlich P. Asa S.L. Brubaker P.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7911-7916Crossref PubMed Scopus (718) Google Scholar, 5Drucker D.J. Shi Q. Crivici A. Sumner-Smith M. Tavares W. Hill M. Deforest L. Cooper S. Brubaker P.L. Nat. Biotechnol. 1997; 15: 673-677Crossref PubMed Scopus (228) Google Scholar). Intriguingly, GLP-1 also exerts trophic effects in the endocrine pancreas, including stimulation of islet ductal neogenesis and β cell proliferation in normal rodentsin vivo and in β cell lines in vitro (6Xu G. Stoffers D.A. Habener J.F. Bonner-Weir S. Diabetes. 1999; 48: 2270-2276Crossref PubMed Scopus (1094) Google Scholar, 7Stoffers D.A. Kieffer T.J. Hussain M.A. Drucker D.J. Egan J.M. Bonner-Weir S. Habener J.F. Diabetes. 2000; 49: 741-748Crossref PubMed Scopus (516) Google Scholar). These actions of GLP-1 and GLP-2 are preserved in experimental models of diabetes and intestinal disease, respectively; hence, activation of glucagon-like peptide receptor signaling pathways leads to enhanced cell proliferation in both normal and injured tissues in vivo. More recent data suggest that the glucagon-like peptides exert direct cytoprotective effects via inhibition of apoptosis either directly in target cells expressing their cognate receptors or indirectly via liberation of as yet unidentified survival factors. GLP-1 inhibits apoptosis in islet β cells or in heterologous baby hamster kidney (BHK) fibroblasts expressing a transfected GLP-1 receptor (8Bregenholt, S., Moldrup, A., Knudsen, L. B., and Petersen, J. S. (2001) 61st Annual Meeting of the American Diabetes Association Philadelphia, June 22–26, 2001, Vol. 50, pp. 125-OR, Abstr. 131, American Diabetes Association, Alexandria, VAGoogle Scholar, 9Hansotia, T., Yusta, B., and Drucker, D. J. (2001) 61st Annual Meeting of the American Diabetes Association Philadelphia, June 22–26, 2001, Vol. 50, pp. 1457-P, Abstr. 1350, American Diabetes Association, Alexandria, VAGoogle Scholar). GLP-2 administration to rodents with experimental intestinal injury markedly attenuates mucosal damage and significantly reduces the extent of apoptosis in both the crypt and enterocyte compartments (10Boushey R.P. Yusta B. Drucker D.J. Am. J. Physiol. 1999; 277: E937-E947Crossref PubMed Google Scholar, 11Boushey R.P. Yusta B. Drucker D.J. Cancer Res. 2001; 61: 687-693PubMed Google Scholar). As enriched populations of intestinal cells or cell lines that express the endogenous GLP-2 receptor (GLP-2R) have not yet been isolated and characterized in vitro, we established a cellular model for analysis of GLP-2R signal transduction in vitro. BHK fibroblasts stably transfected with the rat GLP-2R exhibit dose-dependent cAMP accumulation in response to GLP-2 administration (12Yusta B. Somwar R. Wang F. Munroe D. Grinstein S. Klip A. Drucker D.J. J. Biol. Chem. 1999; 274: 30459-30467Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Remarkably, induction of apoptosis in BHK-rGLP-2R cells with cycloheximide is markedly attenuated by GLP-2, in association with reduced mitochondrial cytochrome c efflux to the cytosol and diminished cleavage and activation of both initiator and effector caspases (13Yusta B. Boushey R.P. Drucker D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the mechanisms stimulated by GLP-2R activation that cAMP accumulation to inhibition of cell we signaling that anti-apoptotic targets following activation of the G protein-coupled and were from phorbol 12-myristate 13-acetate and were from a from insulin from The and the kinase and were from were from The J. Biol. Chem. Full Text PDF PubMed Google a from G. S. BHK fibroblasts the stably of the rat GLP-2R were as (12Yusta B. Somwar R. Wang F. Munroe D. Grinstein S. Klip A. Drucker D.J. J. Biol. Chem. 1999; 274: 30459-30467Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). for cells were in the were for in with to apoptosis induction by the phosphatidylinositol 3-kinase (PI3K) in the in the or of the peptides or for the of as as for phosphorylation of Akt at a of the inhibition of Akt phosphorylation by at not and of with these cell reduced by in the of not hence, not in GLP-2 and insulin were in and and were in were to the as but in the of the in of the The of cells following apoptosis induction by the of at the induction of apoptosis as cells were the with cells in the and in and in with and at and were at for at for with and at the protein and as a of cell were by and The with in and with a primary in and at were with a to and enhanced to at Akt at or p70 S6 kinase at protein kinase at and at Ser21 and respectively; and GSK-3β at Ser9 were at to the of the to Akt, and were at at c at at β-catenin were at and were at The and were to and on on a and of BHK-rGLP-2R cells in to the the cell survival were transfected with of a of or with the of were in for and with in the or of the cells were and activity as (13Yusta B. Boushey R.P. Drucker D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The of activity in these cell death and of the transfected cells D. J. PubMed Scopus Google Scholar). of the phosphorylation of Bad in response to cells were transfected with of the and for a of cells were for in and for in were with the and for analysis as enriched in mitochondrial or were by as (13Yusta B. Boushey R.P. Drucker D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the for analysis as of data were analysis of and were multiple the of signaling for cell we the of the on in BHK-rGLP-2R with a in cell of GLP-2 in the of for significantly cell survival The of GLP-2 on LY294002-induced cell death mimicked by that cAMP a in the of We have that cycloheximide at that by cell death and the and of apoptosis in BHK-rGLP-2R cells (13Yusta B. Boushey R.P. Drucker D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The administration of both and cycloheximide markedly reduced cell to that with either of cells with either GLP-2 or significantly reduced cell death by these that protein is not for the of GLP-2 or on LY294002-induced cell the for coupling of GLP-2R activation to a in cell of cells were with following either GLP-2 or at to analysis of cell of as in B. GLP-2 and significantly enhanced cell at The of for inhibition of in BHK-rGLP-2R cells the for the by the phosphorylation of the protein kinase Akt, a downstream target of signaling 1999; PubMed Scopus Google Scholar). As phosphorylation at and is and for the activation of Akt, we phosphorylation to Akt as a of activation in vitro. analysis of BHK-rGLP-2R cells with a Akt phosphorylation from to following to In contrast, of abrogated the phosphorylation of Akt the of the These results the of as of PI3K/Akt signaling in BHK-rGLP-2R The of by preserved phosphorylation in BHK-rGLP-2R cells in the or of with BHK-rGLP-2R cells with cell including cell and as well as cell B. Boushey R.P. Drucker D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google and data not reduced cell is with of we mitochondrial of cytochrome c and, activation by the cleavage of effector in the and of LY294002. with reduced of Akt and cleavage of poly(ADP-ribose) and β-catenin A and these effects were by the In contrast, cells with and either GLP-2 or preserved of Akt and reduced cleavage of poly(ADP-ribose) and β-catenin of BHK-rGLP-2R cells also with in the of that reduced by GLP-2 or these demonstrate that GLP-2 enhances cell survival and reduces mitochondrial and the cleavage of downstream targets of caspases in a and manner. of the GLP-1 and GLP-2 receptors leads to of and activation of protein kinase A (PKA) (1Drucker D.J. Endocrinology. 2001; 142: 521-527Crossref PubMed Scopus (310) Google Scholar). In the of GLP-2 reduces activation and enhances cell survival in a (13Yusta B. Boushey R.P. Drucker D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the in BHK-rGLP-2R cell not by GLP-2 or in the of the A death to the of the GLP-2 on cell survival in the of LY294002. were with the or in with a a of J. Biol. Chem. Full Text PDF PubMed Google and to with or GLP-2 or The of activity in cells a for the of transfected a in gene activity cell death D. J. PubMed Scopus Google Scholar). In to the of activity in cells with with the or of activity in BHK-rGLP-2R cells to that activity is for the of GLP-2 and on LY294002-induced cell These results that the and of BHK-rGLP-2R cells from LY294002-induced apoptosis but independent of Akt as is a and of and Akt activation the experimental for cAMP and have been to a activation of Akt that is on but not C. B. Biol. 1999; PubMed Scopus Google Scholar, B. 1997; PubMed Scopus Google the that survival in BHK-rGLP-2R cells via of GLP-2 Akt in BHK-rGLP-2R we cells with GLP-2 or for following the phosphorylation of Akt by insulin of BHK-rGLP-2R cells Akt phosphorylation within phosphorylation of Akt at the that the kinase following with or GLP-2 the were in the of the of Akt were markedly and for either or Akt phosphorylation not These suggest that Akt not the survival effects of in BHK-rGLP-2R As p70 S6 kinase is a downstream effector of and regulate in cell proliferation or apoptosis M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google we GLP-2 p70 S6 kinase in the or of S6 kinase as the activity of p70 S6 kinase in vivo most with the phosphorylation of M. C. A. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). insulin phosphorylation of p70 S6 kinase in BHK-rGLP-2R in following of cells to or GLP-2 p70 S6 kinase phosphorylation in the or of GLP-2 or not we GLP-2 exert effects on cell survival via activation of p90Rsk, a kinase that exerts anti-apoptotic effects on downstream as Bad C. L. G. P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. M.A. Science. 1999; PubMed Scopus Google Scholar). phorbol stimulated phosphorylation of at is for the activation of kinase J. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google GLP-2 or on phosphorylation in the not or of LY294002. the mechanisms the reduced cell survival in BHK-rGLP-2R cells and to that control cell we the phosphorylation of a downstream target of both the PI3K/Akt S. P. J. 2001; PubMed Scopus Google and Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar, M. 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Wang Biol. 2000; PubMed Scopus Google Scholar). of BHK-rGLP-2R cells with a in the of Akt by a in the of GSK-3α and GSK-3β at Ser21 and of BHK-rGLP-2R cells with GLP-2 and, to a with the of GSK-3α and GSK-3β at Ser21 and and The of GLP-2 and to of by and for as a downstream effector GLP-2R signaling to phosphorylation independently of p90Rsk, and p70 S6 and phosphorylation of in a PI3K-independent, PKA-dependent in BHK-rGLP-2R were for with or stimulation by GLP-2 and for the were and analysis to to GSK-3α phosphorylation at GSK-3β phosphorylation Ser9 for the β of and were by the with in are the of GSK-3α and GSK-3β from the in A and by as and to the phosphorylation at are of independent The data that GLP-2 cell survival in the of via thereby cell inhibition of either or by with been to apoptosis by inhibition of M. Cooper J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. D. 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J. 2000; PubMed Scopus Google of BHK-rGLP-2R cells with stimulates through the activation of enhanced Bad phosphorylation at Ser155 Bad phosphorylation Akt also been to a Bad Ser155 kinase A., L. A. 2000; Full Text Full Text PDF PubMed Scopus Google however, of the cells Akt in Bad Ser155 yet as phorbol the of Bad at and also as a Bad kinase C. L. G. P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. M.A. Science. 1999; PubMed Scopus Google Scholar). These results suggest that not is a Bad Ser155 kinase in BHK-rGLP-2R the prosurvival effects of GLP-2 and following inhibition of are to Bad the of Bad at in cells with LY294002. The results of these that both GLP-2 and the of Bad at Ser155 independently of the or of As the of cell survival following to we the extent of Bad Ser155 phosphorylation in BHK-rGLP-2R cells with or the analysis that the GLP-2 stimulation of Bad Ser155 phosphorylation abrogated in BHK-rGLP-2R cells with of Bad at Ser155 been to the of Bad to prosurvival of Bad from the mitochondrial to the A., L. A. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). phosphorylation of Bad at Ser155 to the prosurvival effects of GLP-2 and following LY294002-induced to of endogenous Bad from the a in the of Bad to the mitochondrial both GLP-2 and significantly reduced Bad In response to a pro-apoptotic that is in the to the cytochrome c Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, J.M. Q. L. D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). of cells to the of Bax of Bad in the or of GLP-2 or and with the of cytochrome c in the cytosol these results suggest that GLP-2 of the pro-apoptotic Bad and Bax from the to the cytoprotective actions of GLP-2 following inhibition of PI3K/Akt signaling in BHK-rGLP-2R The that GLP-2 attenuates cellular injury in vivo at activation of the GLP-2R a prosurvival signal either indirectly in the intestinal or directly in cells expressing the The GLP-2R been to of cells in the small and bowel B. L. Munroe D. G. R. S. L. Asa S.L. Drucker D.J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast, the GLP-2R is not in intestinal endocrine but GLP-2R have been to by in M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). As enriched populations of cells or that express endogenous GLP-2R have not yet been isolated for vitro, we the direct effects of GLP-2R signaling in BHK fibroblasts stably transfected with the We on the of the in the control of as the PI3K/Akt been to for survival in experimental A. 2001; PubMed Scopus Google Scholar). GLP-1 and GLP-2 in target cells and are to signal through a (1Drucker D.J. Endocrinology. 2001; 142: 521-527Crossref PubMed Scopus (310) Google Scholar). As of cAMP cell through a and C. B. Biol. 1999; PubMed Scopus Google Scholar, A. 2001; PubMed Scopus Google we that GLP-2 to LY294002-induced cell death to the of and Akt for control of cell Remarkably, both GLP-2 and attenuated cell death in the of the of Akt These are with data of cAMP Akt independently of in cells J. S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Akt is not for the prosurvival effects of as cAMP suppress activation and apoptosis in independently of Akt activation J. S. J. 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Physiol. 2001; Scopus Google Scholar). is for cell survival in BHK-rGLP-2R is to not of the following activation of the GLP-2R signaling in cell and Akt downstream targets for control of cell including and A. 1999; PubMed Scopus Google Scholar). GLP-2 and enhanced Bad phosphorylation at Ser155 in BHK-rGLP-2R cells in a manner, that of cell survival in by of Bad with and the of anti-apoptotic of the as A., L. A. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, G. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). and p70 S6 kinase have been as of Bad phosphorylation M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google G. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. P. J. 2000; PubMed Scopus Google we not for or phosphorylation of these in BHK-rGLP-2R In contrast, the phosphorylation of Bad at Ser155 with the of for of Bad activity at G. J. Biol. 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(2001) 61st Annual Meeting of the American Diabetes Association Philadelphia, June 22–26, 2001, Vol. 50, pp. 125-OR, Abstr. 131, American Diabetes Association, Alexandria, VAGoogle R.P. Yusta B. Drucker D.J. Am. J. Physiol. 1999; 277: E937-E947Crossref PubMed Google Scholar, 11Boushey R.P. Yusta B. Drucker D.J. Cancer Res. 2001; 61: 687-693PubMed Google Scholar, B. Boushey R.P. Drucker D.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, B. R. J. M. B. Am. J. Physiol. 2000; PubMed Google Scholar, J. Res. 2000; PubMed Scopus Google data the of GLP-2R signaling a of that cellular injury for of the downstream anti-apoptotic by signaling in cell

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